Investigations and tests

In reaching a diagnosis your doctor will first consider the symptoms and their progression over time, the past medical history, family illnesses and also examination findings. In prion diseases the early symptoms can be shared with many other common illnesses, such as insomnia, altered mood, unusual behaviour, dizziness, or tingling of part of the body. Depending on which symptoms and examination findings predominate in the early stages, your doctor might refer you to a neurologist, psychiatrist or other physician for help. At this first specialist appointment, prion diseases are not always considered because they are rare and the typical signs may not be present, but problems with thinking skills or balance will certainly be noted.

Several investigations may be used to narrow down possible diagnoses, including brain scans (often magnetic resonance imaging or MRI), brain wave tests (electroencephalogram or EEG), spinal fluid tests (cerebrospinal fluid), and blood tests looking for a wide range of biochemical and metabolic disorders, vitamin deficiencies, signs of viral infection, specific antibody tests and thyroid problems. Genetic tests may be requested looking for changes in the DNA causing inherited disorders. Information about some of these tests can be found by following links below. It can take time for these to be done and interpreted.

For many years several research groups and commercial organisations have been trying to develop a simple blood test to diagnose prion diseases. Used in the right way, this could lead to earlier and more accurate diagnosis. In February 2011 the MRC Prion Unit announced a prototype blood test for variant Creutzfeldt-Jakob disease which is described in the section below.

A blood test for variant Creutzfeldt‐Jakob disease (vCJD) has been an important goal of medical research laboratories and companies around the world for many years. It has been very difficult to achieve because the infectious agent (germ) causing vCJD, known as a prion, has unique features that mean that the sensitive methods doctors normally use to detect the presence of a germ (detecting the body’s antibody response to the germ or the germ’s own genetic material) do not work.

The Medical Research Council (MRC) Prion Unit, working with the NHS National Prion Clinic at the National Hospital for Neurology and Neurosurgery (NHNN) in London, has now developed an entirely new type of test following a number of years of intensive research.

The test is at an early (prototype) stage but is able to correctly identify the large majority of patients with symptoms of vCJD and has not yet given any false results in patients with other brain diseases or in healthy individuals. We think this is an important breakthrough and it raises a number of issues which need to be carefully considered. Details of the test have been published by the leading medical journal, the Lancet, on 3rd February 2011. The full text of the paper is available here.

This brief article describes CJD and other so‐called prion diseases, why a blood test is important, how the test works and how to approach us at the National Prion Clinic to inquire further about this test. It is important to be cautious about this news, because although the results so far are very encouraging, we want to go on to look at blood samples from much larger numbers of healthy people and those with other brain diseases to get a better idea of how specific the test is in practice. This will be vital before a version of this test could be considered to routinely screen healthy blood donors.

What are prion diseases?

Also known as transmissible spongiform encephalopathies, prion diseases are a group of rare fatal conditions affecting the brain. Prion diseases are caused by one of the body’s normal proteins, called the prion protein, changing its shape and forming clumps of protein in the brain. This process damages and eventually kills brain cells. In humans, there are three different ways these diseases can start. The commonest form is called sporadic CJD and this form is seen all over the world and appears to occur at random as an unlucky event when the production of prions in the brain is triggered spontaneously. Secondly, the disease can be passed down from generation to generation as a genetic condition in some families with a faulty prion protein gene. Thirdly, and most importantly from the point of view of this new test, someone can “catch” a prion infection by being exposed to infectious prions.

These illnesses affect both animals and humans. The animal prion diseases include scrapie, a common prion disease affecting sheep and goats which is not thought to pose a threat to human health and bovine spongiform encephalopathy (BSE or mad cow disease) in cattle which can jump species to infect humans. BSE prions are responsible for variant CJD which was first recognised in 1996 and which has so far affected about 200 people, most from the UK. It is thought that people become infected by BSE prions by eating food containing material from BSE‐infected cattle, although other sources of exposure are possible. Much of the UK population born before 1996 (when rigorous measures to limit exposure were enforced) have potentially been exposed to BSE‐contaminated food and the number of people who may carry the infection but remain healthy is unknown.

Why is a blood test important?

vCJD (as with other forms of CJD) tends to be diagnosed only when the patient has had the disease for some time and has developed symptoms that are associated with extensive damage to the brain. There are several reasons why this is the case. The early symptoms of the disease (such as anxiety, depression and tingling pains in the legs) have many much more common causes and so doctors will understandably not attribute these symptoms to something much more serious until other features such as difficulty with movement or balance and loss of mental abilities occur. At this stage, it will be apparent there is a serious brain condition but a series of tests are required to make the diagnosis and these take time to organise and interpret. Because the disease itself typically progresses quite rapidly (over weeks and months), the patient is likely to be showing quite advanced symptoms by the time a confident diagnosis is reached. A simple blood test gives us an opportunity to make the diagnosis at a much earlier stage. While at present there is no treatment we know is effective in stopping progression of these diseases, an early diagnosis does avoid the need for other tests and gives the patient and their family a clear answer. This enables them to make the best use of their time together and spend less of this precious time in hospital. However, experimental drugs are being developed at the MRC Prion Unit and elsewhere with a view to clinical trials in the next few years and we would want to try such treatments at the earliest stage before irreversible brain damage has occurred.

It is now known that vCJD can be passed on by blood transfusion. Several vCJD patients had been blood donors before they developed symptoms of the disease. To date, three individuals who had received blood transfusions from such donors have themselves developed and died from the disease. A further individual, who had also received prion‐infected blood, died of unrelated causes but showed evidence of prion infection at autopsy examination.

Only a very small number of individuals are definitely known to have received such potentially infected blood transfusions. However, several thousand individuals have been notified by the Health Protection Agency that they have received possibly infected blood products such as plasma, clotting factors, or purified antibodies. One individual who had received a clotting factor from a donor who went on to get vCJD died of unrelated causes but showed signs of vCJD infection at autopsy. It is not known whether this individual would have gone on to develop the disease had he not died of other causes.

Prion diseases are known to exist in “carrier states” in laboratory animals and these would be expected in humans too. A “carrier” is a person infected with prions but who does not show any signs of disease in their natural lifetime. Such carrier states are well recognised with other infectious diseases in humans. In the UK population, following an anonymous study of archived tissue specimens, the Department of Health uses an estimate that 1 in 4000 individuals may be silently infected with vCJD prions in its risk calculations. There is considerable uncertainty about this figure, that is, the true number could be significantly higher or lower than 1 in 4000. It is also not known how many of those infected will eventually go on to develop the disease itself. We do know that incubation periods in human prion diseases can be very long, over 50 years in some cases. As these infected but healthy individuals cannot currently be identified in the population, many will be active blood donors and could pass on infection to other people in this way or by medical and surgical instruments used on them becoming contaminated by prions (since prions are quite resistant to normal sterilisation methods). The National Blood Service has taken several actions to try to minimise this risk, for example, by removing white cells from blood, however it is uncertain how effective these measures are at reducing risk, or indeed whether they are really justified should the real number of infected people turn out to be extremely small.

A future development of our blood test may allow us to screen donated blood and further increase the safety of blood transfusions. Also it may in the future allow individuals who have been exposed to vCJD infection to find out if there is evidence that the infection has taken hold in their body. However, considerable further research will need to be done first to find out how specific the test is when tested on large numbers of health donors and to understand how good the test will be at detecting infected blood from healthy individuals rather than those with the established disease.

How well does the test work?

It has been hard to develop a test for prion disease because the body’s immune system does not fight off prion infection by making antibodies (that can be readily detected in a blood test) in the same way it does against germs like bacteria or viruses. It has been challenging to develop a test that can distinguish between the normal prion protein, which we all have in our blood, and the abnormal form linked to the disease which is chemically very similar.

Scientists in the MRC Prion Unit have developed a prototype test. This involves taking a small blood sample from a patient as with any other blood test. A small sample of blood is mixed with special metal beads to which the rogue prion proteins stick tightly. These are then washed to remove the normal prion protein and other blood components that would interfere with the test. Finally, the amount of rogue prion protein attached to the beads is measured using antibodies we have developed that bind very tightly to the prion protein.

The test was applied to a number patient samples including from patients with vCJD, those withsporadic CJD, other neurological diseases that might be confused with vCJD and a number of healthy blood donors. As vCJD is a rare disease, only relatively small numbers of samples were available for this testing. All samples were given code numbers and the scientists carrying out the test in our laboratory did not know which sample was which. We were able to try the test on 21 samples from different vCJD patients. 15 of these 21 patient samples (around 70%) were shown to be positive by the test. So far, all samples from other neurological diseases or healthy blood donors have tested negative but only relatively small numbers of these have been looked at so far (about 200). We are testing larger numbers of samples now. At present the test does not work in other forms of prion disease such as sporadic CJD but we are hoping this will be possible with further work in the future.

What happens now and how is the test going to be made available?

We are ready to use the test to assist with diagnosis of patients who are suspected of having vCJD or other diseases that might be mistaken for vCJD. Working with neurological colleagues to begin to use the test will also help us get more information on the test itself and hopefully lead to further improvements and understanding of its usefulness. A request card needs to be completed which can be obtained here. We require at least 2 x 5ml EDTA vacutainer tubes. For sample delivery please see further details here. While we are working to increase the throughput of the test, at this stage it remains relatively labour intensive. Whilst we will attempt to return results at the earliest opportunity, clinicians should allow up to four weeks for results. Please call the Clinic for further details.

The National Prion Clinic at the National Hospital for Neurology is happy to take telephone enquiries about suspected prion disease patients. We are particularly interested in referrals of patients at an early stage of their illness when diagnosis is most difficult.